HER-2/NEU ALTERATIONS IN BREAST AND OVARIAN CANCER

乳腺癌和卵巢癌中的 HER-2/NEU 改变

• 批准号: 6657487
• 负责人: DENNIS J SLAMON
• 金额: $ 18.15万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-09-16 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6657487
• 关键词: MCF7 cell; antineoplastic antibiotics; biological signal transduction; breast neoplasms; enzyme activity; gene expression; gene mutation; growth factor receptors; heregulin; human tissue; immunocytochemistry; intravital microscopy; microarray technology; mitogen activated protein kinase; monoclonal antibody; neoplasm /cancer genetics; neoplastic transformation; northern blottings; ovary neoplasms; phosphatidylinositol 3 kinase; polymerase chain reaction; protein tyrosine kinase; protooncogene; receptor expression; transforming growth factors; vascular endothelial growth factors; western blottings

DESCRIPTION (provided by applicant): The human HER-2/neu gene encodes a growth factor receptor which belongs to the type I receptor tyrosine kinase family. It is now generally accepted that the alteration of this gene plays some critical role in the pathogenesis of the 25-30 percent of human breast cancers in which is it amplified and overexpressed causing the cancers to behave particularly aggressively in patients. As a result of this observation, this genetic alteration has been successfully targeted using the monoclonal antibody Herceptin which is directed against the extra cellular domain of the receptor. During the prior period of support of this project, many of the phenotypic abnormalities associated with this alteration have been identified and shown to be consistent with an aggressive clinical phenotype, i.e. increase growth in vitro, increased tumorigenicity in vivo and increase metastatic potential in orthotopic implantation models. The molecular pathways and mechanisms by which these phenotypic changes are mediated, however, remain only partially elucidated. It is the purpose of this proposal to continue and expand research efforts directed at dissecting the molecular events downstream of this alteration in order to gain a better understanding of this event and perhaps identify molecular targets that would make therapeutic approaches to this alteration even more effective. To that end, four specific aims will be undertaken, including. The further characterization of signaling pathways associated with HER-2/neu overexpression, as well as the similarities and differences in these pathways induced by an agonist (heregulin, NDF) and an antagonist (Herceptin); the expansion on data generated from Specific Aim I to evaluate the changes in the PI3 kinases signaling pathway related to the AKT 2 sgne which appears to be important in the HER-2/neu phenotype; the identification of differentially expressed genes in HER-2 overexpressing versus matched non-overexpressing cells, as well as cells treated with an agonist (heregulin) and antagonist (Herceptin); and finally the characterization of any unique genes identified at the protein and cellular levels, i.e. identification of the encoded protein, characterization of its half life, expression pattern in normal and malignant tissues, and functional studies if indicated.

描述（由申请人提供）：人类HER-2/NEU基因编码生长 属于I型受体酪氨酸激酶家族的因子受体。 现在，人们普遍认为，该基因的变化扮演了一些 25-30％的人乳腺癌的发病机理中的关键作用 它在其中放大和表达过表达，导致癌症行为 特别是在患者中积极进取。由于这个观察， 遗传改变已通过单克隆成功靶向 抗体赫蒂汀，该抗体针对额外的细胞结构域 受体。在此项目的前期，许多 已经确定了与此改变相关的表型异常 并显示与侵略性临床表型一致，即 体外增长增加，体内肿瘤性增加并增加 矫形植入模型中的转移潜力。分子 这些表型变化被介导的途径和机制， 但是，仅部分阐明。这是该提议的目的 继续并扩大旨在剖析分子的研究工作 为了获得更好的理解，该改动的下游事件 在此事件中，也许可以确定会导致的分子靶标 治疗方法更有效。为此， 将进行四个具体目标，包括。进一步的表征 与HER-2/NEU过表达相关的信号通路以及 激动剂引起的这些途径的相似性和差异 （theheygulin，ndf）和对手（赫赛汀）；数据扩展 从特定目的I产生以评估PI3激酶的变化 信号通路与Akt 2 Sgne相关，这似乎很重要 HER-2/NEU表型；鉴定差异表达的基因 在HER-2中过表达与匹配的非过表达的单元格，以及 用激动剂（Thee -Gulin）和拮抗剂（Herceptin）处理的细胞；和 最后，在蛋白质和 细胞水平，即鉴定编码的蛋白质，表征 其半寿命，正常组织和恶性组织中的表达模式，以及 功能研究（如果指示）。